The long-term objective of this application is to develop effective new antiviral drugs for the treatment of Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) caused by the hantavirus. Viruses in the Hantavirus genus, family Bunyaviridae, are high priority Category A viral hemorrhagic fever agents that poses a risk to national security. To date, more than 20 hantaviruses have been described, half of which cause HFRS or HPS. Approximately 150,000 to 200,000 hospitalized cases of HFRS are reported each year throughout the world, with more than half typically occurring in China. The rest are found throughout other parts of Asia, Europe, Russia and Scandinavia. Mortality rates for HFRS vary from 1%-15%, depending in part on which hantavirus caused the infection. The prototype HFRS-hantavirus, Hantaan virus (HTNV), was isolated in 1976 from the lungs of an infected Korean field mouse (Apodemus agrarius). The Sin Nombre virus, the prototype HPS-hantavirus, was first isolated from New Mexico, and has mortality rates of approximately 40%. No licensed vaccines are available for the prevention of HFRS or HPS, and therapeutic efforts are generally limited to supportive care. Our approach for the development of new hantavirus antiviral drugs is guided by mechanistic biochemistry to design and synthesize a series of novel compounds that target the viral replication and transcription pathways. The Specific Aims of this project are 1) to synthesize combinatorial libraries of antiviral drug candidates; 2) to determine the compounds antiviral activity using cell culture and virion-based assays with SNV and HTNV; 3) to conduct systematic chemical modification and in vitro evaluation of resulting change in antiviral activity profile to develop a quantitative structure activity relationship model (QSAR), that will lead to the development of highly active analogs for therapy.